tbuckley/cabot-search huggingface dataset:
Abstract 14945: Geographic Disparity in Mortality From Aortic Diseases in the United States
Authors: Yoshihiro Tanaka, Philip Greenland
Journal: Circulation (2022)

Introduction: Aortic diseases (AD) have a high mortality rate. Previous studies have reported that winter season and/or lower temperature climates were associated with a higher incidence of hospitalization due to AD. It remains unclear whether this observation can be translated into higher mortality rate in the country level. Hypothesis: We hypothesized that AD mortality might be higher in areas of the United States with colder climates or longer winter seasons. Methods: The underlying cause of death file in the CDC WONDER online database was queried between 2015 and 2019. AD deaths were identified by listing aortic aneurysm and dissection (ICD-10 code: I71) as underlying cause of death among persons aged ≥ 35 years. We calculated age-adjusted mortality rate (AAMR) at the Census region level and stratified by sex and race-ethnicity groups (non-Hispanic White, non-Hispanic Black, and Hispanic) per 100,000 population. Adjusted linear regression model by sex and race/ethnicity groups was used to examine the association between AAMR and Census region. We also calculated state-level AAMR of AD, and compared AAMRs in top-5 warmest states with those in the top-5 coldest states in winter. Results: A total of 46,708 AD deaths were identified between 2015 and 2019. AAMR in Midwest was the highest (4.7), followed by West (4.0), Northeast (3.8), and South (3.7). In comparison with South as a referent, Midwest was significantly associated with higher AAMR after adjusting for gender and race/ethnicity groups (beta coefficient: 0.87 [95% confidence interval: 0.37 - 1.37], p-value = 0.002). State-level AAMR seemed higher in northern part of the US and AAMRs were significantly higher in the coldest states compared with the warmest states in winter (p &lt; 0.05) (Figure). Conclusion: The present study showed that the states with colder climates in winter season was significantly associated with higher AAMR in, suggesting that geographical factors are likely to affect the mortality rate in AD.
Abstract 14926: VT LVAD Score and Survival Free From Ventricular Arrhythmias: The University of Michigan Experience
Authors: John Larson, Keerthi Gondi, Amrish Deshmukh, Thomas Cascino, Michael Ghannam, Frank Bogun, Francis D Pagani, Jackson Liang
Journal: Circulation (2022)

Introduction: Ventricular arrhythmias (VA) are a common complication after left ventricular assist device (LVAD) implantation and contribute to increased mortality. The VT LVAD Score was created to help stratify patients into four risk categories: Low Risk, Moderate Risk, High Risk, and Very High Risk. Hypothesis: We sought to assess the performance of the VT LVAD score at our institution. Methods: Consecutive patients who underwent LVAD placement from 2015-2019 were reviewed. VT LVAD scores were correlated with VA free survival (VA-FS). Only 1 patient was in the low-risk group and was excluded from analysis. Results: A total of 237 patients who underwent LVAD implant (age 57.9 ± 14.6 years, 180 male, 89 ischemic cardiomyopathy, 102 with prior VAs, 102 Heartmate 3) were included. Of the 5 variables included in the VT LVAD score, only prior VA was associated VA-FS (HR 3.09[1.89-5.03], p&lt;0.001 (Figure 1A), log rank p=0.003, Figure 1D). There was a significant difference in VA-FS between moderate versus both high and very high-risk groups (p=0.033 and p=0.029 respectively) as well as moderate vs high/very high-risk combined (p=0.041, Figure 1B). The significant difference in VA-FS between moderate vs high/very high-risk score groups persisted among all patients with prior VA (p=0.04, Fig 1C). No other between-group differences in VA-FS were seen (Figure 1B and 1C, p&gt;0.05 for all). Conclusions: Patients with a VT LVAD score of high or very high-risk had worse survival free from VA than patients with moderate-risk score, no other between group differences were noted. History of VA is a simple and powerful risk factor for late VA post LVAD.
Abstract 14846: Reduced Daily Steps Walked and Increased Sedentary Time During Covid 19 Might Have Contributed to Poorer Prognosis in Outpatients With Cardiovascular Disease
Authors: Akihiro Hirashiki, Atsuya Shimizu, Manabu Kokubo, Kenichiro Nomoto, Izumi Kondo, Hidenori Arai
Journal: Circulation (2022)

Introduction: The 2019 coronavirus (COVID-19) pandemic has caused high rates of morbidity and mortality worldwide. Rates of physical activity in older adults may have decreased because of the COVID-19 pandemic, but the extent of this decrease and its effect on prognosis in cardiovascular disease (CVD) remain unknown. Our objective was to investigate the change in physical activity between autumn 2019 (before COVID-19) and autumn 2020 (during the third wave of the pandemic) in older Japanese adults with CVD. Methods: This was a single-center prospective observational study of CVD patients regularly attending our hospital’s cardiology outpatient clinic. We asked questionnaires regarding physical activity at two time points: autumn 2019 and autumn 2020. Patients were followed for an average of 429 days from autumn 2020. Composite endpoints were defined as hospitalization for heart failure, dehydration, cerebral stroke, fall-related fracture, or pneumonia, or all-cause death. Results: The study participants’ (n = 533) mean age was 75.9 years. We found a significant decrease in total steps walked/day in autumn 2020 (4055 steps/day) compared with autumn 2019 (4649 steps/day) ( P &lt; 0.001). Time spent sedentary was significantly longer in autumn 2020 (5.7 h/day) than in autumn 2019 (5.1 h/day) ( P &lt; 0.001). Classification of patients according to steps/day (&lt;2000, 2000 to 4999, or ≥5000 steps/day) in autumn 2020 revealed that cumulative event-free survival was significantly lower in the &lt;2000 steps/day group than in the other two groups (P&lt;0.001, Figure ). Similarly, when patients were classified according to time spent sedentary (˂3, ≥ to ˂6, or ≥6 /day), cumulative event-free survival tended to be lower in the &lt;3 h/day group ( P =0.075). Conclusions: Steps walked/day decreased significantly, and time spent sedentary increased significantly, during COVID-19 in CVD outpatients. Lifestyle changes seem to have affected overall prognosis.
Abstract 15216: Right Ventricular Dysfunction Predictors and Prognostic Value in Ischemic and Non-Ischemic Cardiomyopathies: A Cardiac Magnetic Resonance Study
Authors: Tom Kai Ming K Wang, Duygu Kocyigit, Nicholas Chan, Jennifer Bullen, Zoran B Popovic, Wai Hong W Tang, Brian P Griffin, Scott D Flamm, Deborah H Kwon
Journal: Circulation (2022)

Background: Cardiac magnetic resonance imaging (CMR) is the reference standard for right ventricle (RV) quantification, however predictors and prognosis of RV dysfunction in cardiomyopathy patients, including differences between ischemic (ICM) and non-ischemic (NICM) cardiomyopathies, remain not well understood. We evaluated the factors and outcomes associated with CMR-derived reduced RV systolic function, and compared by type of cardiomyopathy. Methods: Adult cardiomyopathy patients undergoing CMR with RV quantified during 2002-2017 were retrospectively studied. Multivariable linear and Cox regression were used to identify factors associated with reduced RV ejection fraction (RVEF) and the primary endpoint (all-cause death, heart transplant or LVAD) during follow-up. Results: Amongst 771 ICM and 624 NICM patients (mean ages 62.3±11.2 and 52.8±15.9 years, 190 (24.6%) and 253 (40.5%) were female respectively), mean RVEFs were 43±14% and 43±13% respectively. The primary endpoint occurred in 455 (59.0%) ICM and 113 (18.1%) NICM patients over mean follow-up of 5.3±4.5 years. Predictors of lower RVEF in ICM were younger age, lower eGFR, lower left ventricular ejection fraction, higher right ventricular end-diastolic volume indexed and higher mitral regurgitant fraction; and in NICM were male sex, NYHA class III-IV, right bundle branch block, lower left ventricular ejection fraction, higher right ventricular end-diastolic volume and higher mitral regurgitation fraction. Reduced RVEF was associated with the primary endpoint in univariable analysis in both ICM and NICM, but only remained so for NICM in multivariable analysis of the primary endpoint as shown in the table. Conclusion: Reduced RVEF is associated with adverse prognosis, however was only independently associated with the primary endpoint in NCIM but not ICM. Key predictors of RV dysfunction in both ICM and NICM were identified, with some similar and some different predictors between them.
Abstract 14940: Neonatal Cardiac Mesenchymal Stem Cells Target ERK/MAPK Signaling Pathway to Ameliorate Oxidative Stress and Inflammation in Acute Kidney Injury
Authors: Anshuman Sinha, Riley M Boyd, Rachana Mishra, Emily Ciolak, Ling Chen, Sunjay Kaushal, Sudhish Sharma
Journal: Circulation (2022)

Introduction: Failure of multidrug therapy and the multifactorial nature of kidney injury has paved the path way regenerative medicine with over 45 clinical trials using stem cells-based therapy underway. Neonatal cardiac mesenchymal stem cells (nMSC) are one of the most potent stem cells due to their secretome. HYPOTHESIS: SOD2 and anti-inflammatory miRNAs (miR-214 &amp; 95p) in paracrine secretions (secretome) of nMSC provides renoprotection in a rodent model of glycerol-induced AKI. Methods: nMSC were generated from neonatal myocardium using enzymatic digestion and antibodies-based selection. Secretome was collected by conditioning nMSCs for 72 hours in serum free basal medium. Human kidney cells (HKC) were used for in vitro anti-oxidation assays using cisplatin. THP-1 cells were used for anti-inflammatory assessment. CD1 mice were used for glycerol-induced AKI model. Mice were subjected to AKI via IM glycerol (9mg/kg). nMSC-derived secretome was intravenously administered immediately after, or 4 hours post-glycerol. Blood urea nitrogen (BUN) and creatinine were analyzed in serum. Cell survival/KIM1 was assessed by immunohistology/FACS. Other experiments utilized cisplatin toxicity in HKC. Results: Administration of nMSC secretome (5 or 10mg/kg) at the same time or 4-hours post-glycerol administration significantly reduced serum creatinine and BUN in a glycerol induced AKI animal model. Caspase-9 and KIM1 expression was significantly decreased in tubular cells as compared to placebo at a dose of 10mg/kg. KIM-1 was significantly downregulated as compared to placebo following nMSC-secretome administration. Western blot analysis of HKC treated with cisplatin in presence of nMSC-secretome showed significant reduction in NFkb and pERK expression (p&lt;0.05) at 200 μg/ml of nMSC-secretome. IL-8 secretion from macrophages was significantly decreased by nMSC-secretome. Data showing the role of miR-210 in renoprotection will also be shown. Conclusion: nMSC and nMSC-derived secretome provide a renoprotective effect in the setting of glycerol-induced AKI. The mechanism of this effect is driven, at least in part, by a reduction in NfκB and pERK related signaling.
Abstract 15095: A Rare Cardiomyopathy Caught Offsides: Discovery of a New Phenotype
Authors: Nitin Malik, Steven Hsu, Jay A Mazel, Hugh G Calkins, Daniel P Judge, Christopher F Barnett
Journal: Circulation (2022)

A 51-year-old male with Wolff-Parkinson-White (WPW) syndrome, atrial flutter, and third-degree heart block necessitating pacemaker placement presented with asymptomatic atrial flutter. The patient’s father and paternal aunt were diagnosed with WPW and died suddenly at approximate ages of 40 and 60 years, respectively. An echocardiogram showed RV dilation and moderate to severe RV systolic dysfunction with normal LV ejection fraction. Cardiac CT demonstrated thinning of the RV free wall and free wall outpouchings during systole (Figure), as well as moderate asymmetric LV hypertrophy, aneurysmal changes of the basal inferior wall, and dyskinesis of the LV apex. At this time, the differential for RV dysfunction included group 1 pulmonary hypertension, ischemic cardiomyopathy, sarcoidosis, and arrhythmogenic right ventricular cardiomyopathy (ARVC). Subsequent testing excluded all diagnoses other than ARVC. Additionally, 2010 Task Force Criteria for ARVC were not met. However, genetic testing revealed p.Arg302Gln mutation in the PRKAG2 gene. AMP-activated protein kinase (AMPK) is a highly conserved kinase encoded by the PRKAG2 gene that is responsible for controlling cellular energy homeostasis. This PRKAG2 mutation, within the spectrum of genetic mutations resulting in the rare autosomal dominant PRKAG2 syndrome, is characterized by glycogen storage cardiomyopathy and a familial form of WPW, supraventricular arrhythmias, and left ventricular hypertrophy. To the best of our knowledge, this is the first report of PRKAG2 syndrome with prominent abnormalities of the RV, and it expands the scope of PRKAG2 syndrome. Management included implantation of an AICD and ongoing careful monitoring for arrhythmia and heart failure. The patient’s siblings and children were referred for genetic counseling. This case highlights the importance of a broad differential diagnosis and exhaustive evaluation of patients presenting with right ventricular abnormalities.
Abstract 14508: Association of Multi-Ethnic Genome-Wide Blood Pressure Polygenic Risk Score With Adverse Cardiovascular Events
Authors: Vibhu Parcha, Akhil Pampana, Naman Shetty, Marguerite M Irvin, Pradeep Natarajan, Henry Lin, Xiuqing Guo, Stephen S Rich, Jerome I Rotter, Peng Li, Suzanne Oparil, Garima Arora, Pankaj Arora
Journal: Circulation (2022)

Background: Traditional cardiovascular (CV) risk factors and the underlying genetic risk of elevated blood pressure (BP) determine an individual’s composite risk of developing adverse CV events. We evaluated the relative contributions of the traditional CV risk factors to the development of adverse CV events in the context of varying BP polygenic risk score (PRS) profiles among multiethnic population-based cohorts (ARIC, MESA, JHS, FHS, CARDIA, and CHS cohort). Methods: Multiethnic genome-wide BP PRS was constructed among participants with WGS data through TOPMed program and were stratified into high, intermediate, and low genetic risk (&gt;80 th , 20-80 th , &lt;20 th centile). Based on the ACC/AHA Pooled Cohorts Equation (PCE), participants were stratified into low and high (10y-ASCVD risk: &lt;10% or ≥10%) CV risk factor profile groups. Cox regression was used to assess the risk of adverse CV events (incident HF, CHD, and stroke) and its components. Results: Among 21,899 American adults (mean age: 56 years; 56% women; 36% non-White race), 1 SD increase in the BP PRS computed using 1.1 million variants was associated with systolic BP (β: 4.7, 95% CI: 4.5-5.0) and HTN (OR: 1.09, 95% CI: 1.09-1.10), respectively. This association was robustly seen across racial/ethnic groups. Each SD increase in BP PRS was associated with a higher risk of the primary outcome (HR: 1.08 [1.05-1.11]) after controlling for ACC/AHA PCE risk score. Among individuals with a high BP PRS, low ASCVD risk was associated with a 69% lower hazard for the primary outcome (HR: 0.31, [0.27-0.35]) compared with those with high ASCVD risk. A similar pattern was noted in intermediate and low BP PRS groups. Comparable results were noted for all the secondary outcomes. Conclusions: In a multiethnic cohort of &gt;21,000 US adults, genome-wide BP PRS was associated with BP traits and adverse CV events. Adequate CV risk factor control may reduce this increased predisposition to adverse CV events by 69% in those with high BP PRS.
Abstract 15177: Speckle-Tracking Echocardiography Improves Risk Stratification in Patients With Chagas Cardiomyopathy
Authors: Marcelo A Maia, Ester Cerdeira Sabino, José Luiz Padilha da Silva, Lea Oliveira-da Silva, Omar R Santos-Junior, Ana Isabel Nobre Maia, Fellipe Versiani, Ariela Ferreira, Antonio Luiz Ribeiro, Maria C Nunes
Journal: Circulation (2022)

Introduction: Chagas cardiomyopathy is an important cause of death in endemic areas. Speckle-tracking echocardiography (STE)-derived strain is a sensitive tool for evaluating myocardial function which may be helpful to improve risk stratification of Chagas cardiomyopathy patients. This study evaluated whether STE has incremental value for prognosis over traditional clinical and echocardiographic parameters in patients with Chagas cardiomyopathy. Methods: Patients with Chagas disease who had evidence of heart failure were selected for the study. Clinical evaluation, electrocardiogram (ECG), and echocardiogram were performed at the time of enrollment. STE-derived global longitudinal strain (GLS) was analyzed offline. The outcome was all-cause mortality. Results: A total of 317 patients were enrolled, mean age was 66 ± 13 years and 184 (58%) were women. During a mean follow-up of 2.6 years, 114 patients died (36%) with overall mortality incidence rate of 14.0 deaths per 100 patient-years (95% CI 11.6-16.8). GLS was an important predictor of death (HR 0.90; 95% CI 0.86 to 0.95; P&lt;0.001), adding incremental prognostic value to standard echocardiographic parameters including right ventricular (RV) end-diastolic area, E/e’ ratio, left atrial (LA) volume, and left ventricular ejection fraction (LVEF). In overall population, the model including GLS had better accuracy in predicting mortality than the model including only conventional echocardiographic variables (P = 0.015). When the patients were stratified according to LVEF, GLS provided incremental prognostic information in patients with preserved (n=84; HR 0.80; 95% CI 0.64 to 0.98) or with mild to moderate reduced LVEF (n=166; HR 0.92; 95% CI 0.85 to 0.98), whereas in those who had severe LV dysfunction (n=67), GLS was no longer associated with mortality. Conclusions: In a cohort of patients with Chagas cardiomyopathy living in remote areas, GLS was a strong predictor of death, improving risk stratification beyond that provided by standard echocardiographic measurements, especially in patients with non-severe LV dysfunction. STE assessment may be used in a clinical setting to improve the risk prediction model for mortality in patients with Chagas cardiomyopathy.
Abstract 15061: Role of Exosomal Microrna-21a-5p in the Modulation of Ischemia-Induced Angiogenesis in Hypercholesterolemic Conditions
Authors: Nozha Raguema, Sylvie Dussault, Yi Hui Luo, Michel Desjarlais, Alain Rivard
Journal: Circulation (2022)

Introduction: Extracellular vesicles (EVs) and their MicroRNA (miR) content are involved in several physiological processes, including the response to ischemia and angiogenesis. Hypercholesterolemia (HC) is an important cardiovascular risk factor associated with impaired angiogenesis and ischemia-induced neovascularization. However, the effect of HC on the modulation of miR content in EVs in the setting of tissue ischemia is unknown. Hypothesis: We tested the hypothesis that HC causes alterations in the miR content of EVs related to ischemia/neovascularization, and that engineered EVs can be harnessed as angiogenic vectors to promote angiogenesis and therapeutic neovascularization in this situation. Methods: We used a mouse model of peripheral artery disease to induce severe ischemia in the hindlimbs of hypercholesterolemic ApoE -/- and control C57Bl/6J mice. Microvesicles (MVs) and exosomes (exo) were isolated from ischemic skeletal muscles by differential centrifugation. Total RNA was extracted from these 2 types of EVs, and the miR content was analyzed using next generation sequencing. Selected miRs were transfected in EVs and the angiogenic capacity of the engineered EVs was assessed in vitro using a Matrigel assay. Results:: Bioinformatic analysis of the 100 most expressed miRs in EVs showed an enrichment of several miRs in EVs compared to ischemic skeletal muscles. Interestingly the highly expressed miR-21a-5p, which has previously been shown to have angiogenic properties, is specifically enriched in exo. Moreover, we found that miR-21a-5p expression is reduced in exo isolated from ischemic skeletal muscles in hypercholesterolemic conditions. We next forced miR-21a-5p expression in exo, and found that these engineered exo significantly increase tube formation in HUVECs. Conclusions: We show that several angiogenic miRs are enriched in EVs in the setting of tissue ischemia, and that HC can alter EV miR profile in this situation. miR-21a-5p, which expression is reduced by HC, was identified as an important modulator of exo angiogenic activity. Exo engineered to overexpress miR-21a-5p could eventually constitute a novel therapeutic strategy to promote neovascularization and reduce ischemic damages in severe vascular diseases.
Abstract 14506: Re-Evaluating Clinically Relevant Genes in Conotruncal Cardiac Defects by Burden Analyses of Rare and Ultra-Rare Protein-Altering Variants
Authors: Martin Man Chun Chui, Christopher C.Y. Mak, Mullin Yu, Fong Ting Jeffrey Chau, K.S. Lun, T.C. Yung, Anna K.Y. Kwong, Pak-cheong Chow, Brian H.Y. Chung
Journal: Circulation (2022)

Conotruncal cardiac defects (CTD) is a group of congenital heart diseases (CHD) involving malformation of outflow tract, with an estimated prevalence of 11.6 per 10,000 births. Currently, a robust consensus on causative genes for nonsyndromic CTD remains to be elucidated. To prioritize clinically relevant genes in whole exome sequencing (WES), we performed gene burden analysis on rare (gnomAD exome allele frequency &lt; 0.01%) protein-altering variants in a cohort of nonsyndromic CTD (n = 245) comparing with ethnicity and location matched controls (n = 853); and expanded to a combined analysis of damaging ultra-rare (CADD ≥ 20 and absent in gnomAD exome) variants involving four CTD cohorts (n = 1451; 391 Chinese and 1060 Europeans) and ethnicity matched gnomAD exome singletons as controls. Gene burden analysis on variants identified within a high-confidence list of 132 CHD genes showed significant (Bonferroni corrected p-value &lt; 0.05) excess of rare protein-altering variants in two well-established genes ( GATA6 , NOTCH1 ) and four potentially relevant genes for CTD ( ANKRD11 , DOCK6 , NPHP4 , STRA6 ). Furthermore, burden analysis of ultra-rare variants in the combined cohorts identified three genes robustly (Bonferroni corrected p-value &lt; 0.05) associated with CTD ( FLT4 , NOTCH1 , TBX1 ). Predominantly more FLT4 loss-of-function variants were reported in Europeans than in Chinese, while GATA6 was the only gene with robust burden in Chinese but was not identified in Europeans, suggesting potential differences in the genetic landscape of CTD disease etiology among different ethnicities. Our results provided evidence of aggregate variant excess for nonsyndromic CTD in case-control comparisons and shortlisted significant genes with potential clinical relevance for further systematic curation, to guide appropriate genetic diagnosis for CTD with the application of WES.